Limitations of Use

ANDEXXA has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any FXa inhibitors other than apixaban or rivaroxaban.

For intravenous (IV) use only.

There are two dosing regimens (see Table 1). The safety and efficacy of an additional dose have not been established.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1: ANDEXXA Dosing Regimens</span> </caption> <col width="11%"/> <col width="26%"/> <col width="25%"/> <col width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Dose</span><a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></th><th align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Initial IV Bolus </span></th><th align="left" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">Follow-On IV Infusion</span></th><th align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Total Number of 200 mg Vials</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>The safety and effectiveness of more than one dose have not been evaluated.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Low Dose</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">400 mg at a target rate of 30 mg/min</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">4 mg/min for 120 minutes (480 mg)</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">5<br/> (2 vials bolus + 3 vials infusion)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">High Dose</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">800 mg at a target rate of 30 mg/min</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">8 mg/min for 120 minutes (960 mg)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9<br/>(4 vials bolus + 5 vials infusion)</p> </td> </tr> </tbody> </table></div>

The recommended dosing of ANDEXXA is based on the specific FXa inhibitor, dose of FXa inhibitor, and time since the patient's last dose of FXa inhibitor (see Table 2).

Table 2: ANDEXXA Dose Based on Rivaroxaban or Apixaban Dose (Timing of Last Dose of FXa Inhibitor before ANDEXXA Initiation)

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <col width="23%"/> <col width="29%"/> <col width="28%"/> <col width="20%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">FXa Inhibitor</span> </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">FXa Inhibitor</span> </dd> <dt> </dt> <dd> <span class="Bold">Last Dose</span> </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">&lt; 8 Hours or Unknown</span> </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">≥ 8 Hours</span> </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <dl> <dt> </dt> <dd>Rivaroxaban</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>≤ 10 mg</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Low Dose</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" rowspan="4" valign="top"> <dl> <dt> </dt> <dd>Low Dose</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>&gt; 10 mg or Unknown</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>High Dose</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <dl> <dt> </dt> <dd>Apixaban</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>≤ 5 mg</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Low Dose</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>&gt; 5 mg or Unknown</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>High Dose</dd> </dl> </td> </tr> </tbody> </table></div>

IV Bolus Preparation

<div class="scrollingtable"><table width="85%"> <col width="34%"/> <col width="33%"/> <col width="31%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Determine total number of vials required (see <a href="#_RefTable1">Table 1</a>).<br/>200 mg vials:<br/>Reconstitute the 200 mg vial of ANDEXXA with 20 mL of Sterile Water for Injection (SWFI).<br/>Use a 20-mL (or larger) syringe and 20-gauge</p> <p>(or smaller in diameter, e.g., 21-gauge) needle.<br/>Slowly inject the SWFI, directing the solution onto the inside wall of the vial to minimize foaming.<br/>To reduce the total reconstitution time needed during preparation, reconstitute all required vials in succession.</p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="middle"><a name="id416"></a><img alt="Figure" src="/dailymed/image.cfm?name=andexxa-01.jpg&amp;setid=2d9d90a6-63e6-46ef-96ff-dd6519ae7b6c"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">To ensure dissolution of the cake or powder, gently swirl each vial until complete dissolution of powder occurs (A). Do not shake (B); shaking could lead to foaming. Typical dissolution time for each vial is approximately three to five minutes. If dissolution is incomplete, discard the vial, and do not use the product.<br/>Upon reconstitution, the parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration.</p> </td><td align="center" valign="top"> <p class="First"> (A) </p> </td><td align="center" class="Rrule" valign="top"> <p class="First">(B)</p> </td> </tr> <tr> <td align="center" class="Botrule" valign="top"><a name="id424"></a><img alt="figure a" src="/dailymed/image.cfm?name=andexxa-02.jpg&amp;setid=2d9d90a6-63e6-46ef-96ff-dd6519ae7b6c"/></td><td align="center" class="Botrule Rrule" valign="top"><a name="id426"></a><img alt="figure B" src="/dailymed/image.cfm?name=andexxa-03.jpg&amp;setid=2d9d90a6-63e6-46ef-96ff-dd6519ae7b6c"/></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Use 40-mL (or larger) syringe with a 20-gauge (or smaller in diameter, e.g., 21-gauge) needle to withdraw the reconstituted ANDEXXA solution from each of the vials until the required dosing volume</p> <p>is achieved. Note the total volume withdrawn into the syringe.<br/>Transfer the ANDEXXA solution from the syringe into an empty polyolefin or polyvinyl chloride IV bag with a volume of 250 mL or less.</p> </td><td align="center" class="Botrule Rrule" colspan="2" valign="middle"><a name="id431"></a><img alt="figure II" src="/dailymed/image.cfm?name=andexxa-04.jpg&amp;setid=2d9d90a6-63e6-46ef-96ff-dd6519ae7b6c"/></td> </tr> </tbody> </table></div>

Discard the syringe and needle.

Discard the vials, including any unused portion.

Continuous IV Infusion Preparation

Patients treated with FXa inhibitor therapy have underlying disease states that predispose them to thromboembolic events. Reversing FXa inhibitor therapy exposes patients to the thrombotic risk of their underlying disease. To reduce the risk of thrombosis, resume anticoagulant therapy as soon as medically appropriate following treatment with ANDEXXA.

ANDEXXA is available as a white to off-white lyophilized powder in single-dose vials of 200 mg of coagulation factor Xa (recombinant), inactivated-zhzo.

{ "type": "p", "children": [], "text": "ANDEXXA is available as a white to off-white lyophilized powder in single-dose vials of 200 mg of coagulation factor Xa (recombinant), inactivated-zhzo." }

None.

{ "type": "p", "children": [], "text": "None." }

The thromboembolic and ischemic risks were assessed in 419 bleeding -patients in the ANNEXA-4 study who received ANDEXXA and were treated with apixaban or rivaroxaban. There were 45/419 (10.7%) patients who experienced a thrombotic event. The median time to first event was 10 days, and 17 patients experienced the event within three days of treatment. Of the 419 patients who received ANDEXXA, 266 received at least one anticoagulation dose within 30 days after treatment as a prophylactic measure. Of these 266 patients, 14 patients (5.3%) had a thrombotic event after resumption [see Adverse Reactions (6.1)].

Monitor patients treated with ANDEXXA for signs and symptoms of arterial and venous thromboembolic events, ischemic events, and cardiac arrest. To reduce thromboembolic risk, resume anticoagulant therapy as soon as medically appropriate following treatment with ANDEXXA [see Dosage and Administration (2.4)].

The safety of ANDEXXA has not been evaluated in patients who experienced thromboembolic events or disseminated intravascular coagulation within two weeks prior to the life-threatening bleeding event requiring treatment with ANDEXXA. Safety of ANDEXXA also has not been evaluated in patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within seven days prior to the bleeding event.

Unresponsiveness to unfractionated heparin leading to non-prolongation of activated clotting times and serious thrombotic events has occurred following ANDEXXA administration. [see Postmarketing Experience (6.2)].

Do not use ANDEXXA for the reversal of direct FXa inhibitors (apixaban and rivaroxaban) prior to heparinization. If anticoagulation is needed, use an alternative anticoagulant to heparin

Use of ANDEXXA as an antidote for heparin has not been established.

The time course of anti-FXa activity following ANDEXXA administration was consistent among the healthy volunteer studies and the ANNEXA-4 study in bleeding patients [see Clinical Studies (14)]. Compared to baseline, there was a rapid and substantial decrease in anti-FXa activity corresponding to the ANDEXXA bolus. This decrease was sustained through the end of the ANDEXXA continuous infusion. The anti-FXa activity returned to the placebo levels approximately two hours after completion of a bolus or continuous infusion. Subsequently, the anti-FXa activity decreased at a rate similar to the clearance of the FXa inhibitors.

A total of 114 patients from ANNEXA-4 were anticoagulated with apixaban or rivaroxaban and had elevated baseline levels of anti-FXa (>150 ng/mL for apixaban and >300 ng/mL for rivaroxaban). After administration of ANDEXXA, these patients experienced decreased anti-FXa activity levels, with median reductions of 96% for rivaroxaban and 92% for apixaban.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most common adverse reactions (≥ 5%) in bleeding patients receiving ANDEXXA were urinary tract infections and pneumonia.

In Study 3 (ANNEXA-4), four hundred and seventy-seven patients with acute major bleeding were enrolled and received ANDEXXA. Of these 477 patients, 419 patients were treated with apixaban (245/419; 58.5%) or rivaroxaban (174/419; 41.5%). Most patients had received apixaban or rivaroxaban as anticoagulation treatment for atrial fibrillation (348/419; 83%) or venous thromboembolism (65/419; 16%). In the majority of patients, ANDEXXA was used to reverse anticoagulant therapy following either an intracranial hemorrhage (289/419; 69%) or a gastrointestinal bleed (95/419; 23%), with the remaining patients (35/419; 8.4%) experiencing bleeding at other sites. Patients were assessed at a Day 30 follow-up visit following infusion with ANDEXXA.

Deaths

In the ANNEXA-4 study, of the 419 patients in the safety population who were treated with apixaban or rivaroxaban, there were 75 deaths (18%). There were 37 cardiovascular deaths related to bleeding, 19 deaths that were cardiovascular and not related to bleeding, 14 that were non-cardiovascular, and 5 deaths had an uncertain or unknown cause. The average time to death was 15 days after treatment. All patients died prior to Day 45. Of the 75 patients who died, the initial bleeding event was intracranial bleeding in 55 (73%), gastrointestinal bleeding in 14 (19%), and other bleeding types in 6 (8%)patients.

Thromboembolic and Ischemic Events

In the Study 3 (ANNEXA-4), 45/419 (10.7%) patients experienced one or more of the following thromboembolic events: cerebrovascular accident (CVA) (19/45; 42%), deep venous thrombosis (11/45; 24%), myocardial infarction (9/45; 20%), pulmonary embolism (5/45; 11%), and transient ischemic attack (1/45; 2%). The median time to event was ten days. A total of 38% of patients with thromboembolic events (17/45) experienced the thromboembolic event during the first three days. Of the 419 patients who received ANDEXXA, 282 (67.3%) received any form of re-anticoagulation within 30 days after treatment. Of these 282 patients, 16 received anticoagulation in response to a thrombotic event, while 266 received the anticoagulation as a prophylactic. Of these 266, 14 patients (5.3%) had a thrombotic event after resumption of anticoagulation; while of the 153 patients who did not receive anticoagulation as a prophylactic, 31 (20.3%) had a thrombotic event. No patient had a thrombotic event after resumption of oral anticoagulation [see Warnings and Precautions (5.1)].

Infusion-Related Reactions

In the ANNEXA-4 study, 2/419 (0.5%) patients experienced an infusion-related reaction, neither of which were assessed as severe (1 moderate; 1 mild). Reported signs and symptoms were transient and included rigors, chills, hypertension, oxygen desaturation, agitation and confusion.

The following adverse reactions have been identified during post-approval use of ANDEXXA.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or stablish a causal relationship to drug exposure.

General disorders and administration site conditions: heparin resistance [see Unresponsiveness to Unfractionated Heparin (5.2)] and [see Use with Unfractionated Heparin (7.1)].

Unresponsiveness to unfractionated heparin has occurred following ANDEXXA administration, characterized by non-prolongation of activated clotting times and requirement for increased dosing of heparin. Do not use unfractionated heparin following ANDEXXA administration.

Current commercial clinical anti-FXa-activity assays are unsuitable for measuring FXa activity following administration of ANDEXXA. Due to the reversible binding of ANDEXXA to the FXa inhibitor, the high sample dilution currently used in commercial clinical assays promotes dissociation of the inhibitor from ANDEXXA, resulting in detection of erroneously elevated anti-FXa activity levels, thereby causing a underestimation of the reversal activity of ANDEXXA.

Risk Summary

There are no adequate and well-controlled studies of ANDEXXA in pregnant women to inform patients of associated risks. Animal reproductive and developmental studies have not been conducted with ANDEXXA.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Labor or Delivery

The safety and effectiveness of ANDEXXA during labor and delivery have not been evaluated.

Risk Summary

There is no information regarding the presence of ANDEXXA in human milk, the effects on the breastfed child, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ANDEXXA and any potential adverse effects on the breastfed child from ANDEXXA or from the underlying maternal condition.

The safety and efficacy of ANDEXXA in the pediatric population have not been studied.

Of the 419 patients in the ANNEXA-4 study of ANDEXXA, 381 (91%) were 65 years of age or older, and 278 (66%) were older than 75 years of age. No overall differences in safety or efficacy were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between elderly and younger patients; however, greater sensitivity of some older individuals cannot be ruled out.

ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) is a sterile, white to off-white lyophilized powder available in single-dose vials.

{ "type": "p", "children": [], "text": "ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) is a sterile, white to off-white lyophilized powder available in single-dose vials." }

Each 200 mg vial delivers 200 mg of coagulation factor Xa formulated with the inactive ingredients tromethamine (Tris base), Tris hydrochloride, L-arginine hydrochloride, sucrose (1% w/v), mannitol (2.5% w/v), and polysorbate 80 (0.01% w/v) at pH 7.8.

{ "type": "p", "children": [], "text": "Each 200 mg vial delivers 200 mg of coagulation factor Xa formulated with the inactive ingredients tromethamine (Tris base), Tris hydrochloride, L-arginine hydrochloride, sucrose (1% w/v), mannitol (2.5% w/v), and polysorbate 80 (0.01% w/v) at pH 7.8." }

After reconstitution of the lyophilized powder with SWFI for IV administration, the product is a clear, colorless to slightly yellow solution. ANDEXXA contains no preservatives.

{ "type": "p", "children": [], "text": "After reconstitution of the lyophilized powder with SWFI for IV administration, the product is a clear, colorless to slightly yellow solution. ANDEXXA contains no preservatives." }

The active ingredient in ANDEXXA is a genetically modified variant of human FXa. The active site serine was substituted with alanine, rendering the molecule unable to cleave and activate prothrombin. The gamma-carboxyglutamic acid (Gla) domain was removed to eliminate the protein's ability to assemble into the prothrombinase complex, thus removing the potential anticoagulant effects.

{ "type": "p", "children": [], "text": "The active ingredient in ANDEXXA is a genetically modified variant of human FXa. The active site serine was substituted with alanine, rendering the molecule unable to cleave and activate prothrombin. The gamma-carboxyglutamic acid (Gla) domain was removed to eliminate the protein's ability to assemble into the prothrombinase complex, thus removing the potential anticoagulant effects." }

No additives of human or animal origin are used in the manufacture of ANDEXXA. The recombinant protein is produced in a genetically engineered Chinese Hamster Ovary (CHO) cell expression system and has a molecular weight of approximately 41 kDa. The manufacturing process incorporates two validated virus clearance steps.

{ "type": "p", "children": [], "text": "No additives of human or animal origin are used in the manufacture of ANDEXXA. The recombinant protein is produced in a genetically engineered Chinese Hamster Ovary (CHO) cell expression system and has a molecular weight of approximately 41 kDa. The manufacturing process incorporates two validated virus clearance steps." }

Coagulation factor Xa (recombinant), inactivated-zhzo exerts its procoagulant effect by binding and sequestering the FXa inhibitors, rivaroxaban and apixaban. Another observed procoagulant effect of the ANDEXXA protein is its ability to bind to, and inhibit the activity of, Tissue Factor Pathway Inhibitor (TFPI). Inhibition of TFPI activity can increase tissue factor (TF)-initiated thrombin generation.

The effects of ANDEXXA can be measured using assays for its anti-FXa activity, free fraction of FXa inhibitor, and thrombin generation. In addition to its ability to sequester the FXa inhibitors, rivaroxaban and apixaban, ANDEXXA has been shown to inhibit TFPI activity.

The dose and dosing regimen of ANDEXXA that are required to reverse anti-FXa activity and to restore thrombin generation were determined in dose-ranging studies on healthy volunteers. Dosing of ANDEXXA, as a bolus followed by a two-hour continuous infusion, resulted in a rapid decrease in anti-FXa activity (within two minutes after the completion of the bolus administration) followed by reduced anti-FXa activity that was maintained throughout the duration of the continuous infusion [see Clinical Studies (14)]. The anti-FXa activity returned to the placebo levels approximately two hours after completion of a bolus or continuous infusion, whereas TFPI activity in plasma returned to the pretreatment levels approximately 96 hours following ANDEXXA administration.

Elevation of TF-initiated thrombin generation above the baseline range (prior to anticoagulation) occurred within two minutes following a bolus administration of ANDEXXA and was maintained throughout the duration of the continuous infusion. The TF-initiated thrombin generation was elevated above placebo for at least 22 hours. The sustained elevation of thrombin generation over the baseline range and the sustained elevation over placebo were not observed in a contact-activated thrombin generation assay (an assay that is not affected by TF-TFPI interaction).

Laboratory assessment of coagulation does not necessarily correlate with or predict the hemostatic effectiveness of ANDEXXA.

A summary of the pharmacokinetic (PK) properties of ANDEXXA in healthy patients is shown in the table below (see Table 3).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3: Summary of PK Parameters with High and Low Doses</span> </caption> <col width="23%"/> <col width="38%"/> <col width="38%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Low Dose</span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">High Dose</span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">Data presented are geometric mean (Geometric Mean % Coefficient of Variation), [range].</td> </tr> </tfoot> <tbody> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">n</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">AUC<span class="Sub">0-∞</span> </p> <p>(hr*µg/mL)</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">200.5 (16.3)<br/>[153.4; 255.6]</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">572.9 (16.0)<br/>[467.1; 783.9]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">C<span class="Sub">max</span> </p> <p>(µg/mL)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">76.6 (17.5)<br/>[61.1; 100.1]</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">206.6 (18.8)<br/>[158.9; 280.5]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Clearance </p> <p>(L/hr)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4.4 (16.3)<br/>[3.4; 5.7]</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.1 (16.0)<br/>[2.3; 3.8]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">T<span class="Sub">1/2</span> (hr)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.3 (15.0)<br/>[2.3; 4.0]</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2.7 (20.0)<br/>[1.9; 3.4]</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">V<span class="Sub">ss</span> (L)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4.4 (17.6)<br/>[3.3; 5.7]</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.0 (23.3)<br/>[2.2; 5.0]</p> </td> </tr> </tbody> </table></div>

Drug-Drug Interaction

The pharmacokinetics of ANDEXXA were not affected by apixaban (5 mg orally BID for six days) or rivaroxaban (20 mg orally once daily for six days).

The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of ANDEXXA.

Using electrochemiluminescence (ECL)-based assays, 417 ANDEXXA-treated healthy patients were tested for antibodies to ANDEXXA as well as for antibodies cross-reacting with factor X (FX) and FXa. The analysis of available samples up to Day 48 from pooled healthy patients revealed low incidence of anti-ANDEXXA (≤ 8.7%) and anti-FXa (≤ 0.8%) at all timepoints and no anti-FX antibody was detected at any timepoint. The pattern of immunogenicity in patients with acute major bleeding in the ANNEXA-4 study was similar to that observed in healthy patients. Of the 277 ANDEXXA-treated patients in ANNEXA-4 who had available samples at Day 30 or 45, 7.9% (22/277) had antibodies against ANDEXXA, 0.4% (1/277) patients had antibodies against FXa and no patients had antibodies against FX. No neutralizing antibodies against ANDEXXA or cross-reacting with FX or FXa were detected in healthy patients or in bleeding patients.

Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of ANDEXXA have not been fully characterized.

No animal studies were performed to evaluate the effects of ANDEXXA on carcinogenesis, mutagenesis, or impairment of fertility.

Study 1 ANNEXA-A (NCT02207725) – apixaban reversal

In Study 1, healthy patients (median age: 57 years; range: 50 to 73 years) received apixaban 5 mg twice daily for three and a half days to achieve steady-state. At three hours after the last apixaban dose (~ Cmax), ANDEXXA or placebo was administered. Eight patients received placebo, and 24 received ANDEXXA, administered as a 400 mg IV bolus followed by a 4 mg per minute continuous infusion for 120 minutes (total 480 mg).

Study 2 ANNEXA-R (NCT02220725) – rivaroxaban reversal

In Study 2, healthy patients (median age: 57 years; range: 50 to 68 years) received rivaroxaban 20 mg once per day for four days to achieve steady-state. At four hours after the last rivaroxaban dose (~ Cmax), ANDEXXA or placebo was administered. Thirteen patients received placebo, and 26 received ANDEXXA, administered as an 800 mg IV bolus followed by an 8 mg per minute continuous infusion for 120 minutes (total 960 mg).

Reduction in Anti-FXa Activity

In Study 1 and Study 2, the percent change from baseline in anti-FXa activity at its nadir was statistically significant (p < 0.0001) in favor of the ANDEXXA groups compared to placebo in both Studies 1 and 2. The results of Study 1 and Study 2 are provided below (see Table 4).

The time courses of anti-FXa activity before and after ANDEXXA administration are shown in Figure 1.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 4 - A: Change in Anti-FXa Activity/Study 1 (apixaban)</span> </caption> <col width="33%"/> <col width="32%"/> <col width="32%"/> <thead> <tr class="First Last"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Anti-FXa Activity</span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">ANDEXXA</span> <br/> <span class="Bold">n=23</span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Placebo</span> <br/> <span class="Bold">n=8</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Nadir is the smallest value for anti-FXa activity at the 110-minute (ten minutes prior to the end of the infusion) time point, 2-minute time point before completion of the infusion, or the 5-minute time point after the completion of the infusion for each patient.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>The CI is for the Hodges-Lehman estimate of shift.</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">‡</a> </dt> <dd>p-value obtained from a 2-sided exact Wilcoxon rank-sum test.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Mean baseline ng/mL (± SD)</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">173.0<br/>(50.5)</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">191.7<br/>(34.4)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Mean ng/mL (± SD) change from baseline at the nadir<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-160.6<br/>(49.3)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-63.2<br/>(18.1)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Mean % (± SD) change from baseline at the nadir<a class="Sup" href="#footnote-3">*</a> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-92.3<br/>(2.8)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-32.7<br/>(5.6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median difference and associated</p> <p>95% confidence interval (CI)<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-59.5 (-64.1; -55.2)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">not applicable</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">p-value</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">&lt; 0.0001<a class="Sup" href="#footnote-5" name="footnote-reference-5">‡</a> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">not applicable</p> </td> </tr> <tr class="Last"> <td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 4 - B: Change in Anti-FXa Activity/Study 2 (rivaroxaban)</span> </caption> <col width="33%"/> <col width="32%"/> <col width="32%"/> <thead> <tr class="First Last"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Anti-FXa Activity</span></th><th align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">ANDEXXA</span> <br/> <span class="Bold">n=26</span></th><th align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Placebo</span> <br/> <span class="Bold">n=13</span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">SD = Standard deviation.<br/>Note: Baseline is the last assessment obtained prior to the first dose of ANDEXXA or placebo.</td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>Nadir is the smallest value for anti-FXa activity at the 110-minute (ten minutes prior to the end of the infusion) time point, 2-minute time point before completion of the infusion, or the 5-minute time point after the completion of the infusion for each patient.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">†</a> </dt> <dd>The CI is for the Hodges-Lehman estimate of shift.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">‡</a> </dt> <dd>p-value obtained from a 2-sided exact Wilcoxon rank-sum test.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Mean baseline ng/mL (± SD)</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">335.3<br/>(91.0)</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">317.2<br/>(91.0)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Mean ng/mL (± SD) change from baseline at the nadir<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">-324.5<br/>(89.2)</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">-143.4<br/>(58.8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Mean % (± SD) change from baseline at the nadir<a class="Sup" href="#footnote-6">*</a> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">-96.7<br/>(1.8)</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">-44.6<br/>(11.8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median difference and associated</p> <p>95% confidence interval (CI)<a class="Sup" href="#footnote-7" name="footnote-reference-7">†</a> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">-51.9 (-58.0; -47.0)</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">not applicable</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">p-value</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">&lt; 0.0001<a class="Sup" href="#footnote-8" name="footnote-reference-8">‡</a> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">not applicable</p> </td> </tr> </tbody> </table></div>

Figure 1: Change in Anti-FXa Activity (ng/mL) in Patients Anticoagulated with Apixaban (A – Study 1) and Rivaroxaban (B – Study 2)

<div class="scrollingtable"><table width="50%"> <col width="58%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule" valign="top"><a name="id995"></a><img alt="figure a 14" src="/dailymed/image.cfm?name=andexxa-05.jpg&amp;setid=2d9d90a6-63e6-46ef-96ff-dd6519ae7b6c"/></td> </tr> <tr> <td align="center" valign="top"> <p class="First"> <span class="Bold">(A)</span> </p> </td> </tr> <tr> <td align="center" valign="top"><a name="id1002"></a><img alt="figure b 14" src="/dailymed/image.cfm?name=andexxa-06.jpg&amp;setid=2d9d90a6-63e6-46ef-96ff-dd6519ae7b6c"/></td> </tr> <tr class="Last"> <td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">(B)</span> </p> </td> </tr> </tbody> </table></div>

Anti-FXa activity was measured prior to and after ANDEXXA or placebo administration.Dashed lines indicate the end of the bolus or infusion. A break in the x-axis is added to better visualize the immediate, short-term dynamics of anti-FXa activity following ANDEXXA treatment. The points on the graph represent the mean anti-FXa activity level; error bars illustrate standard error. There was a statistically significant difference (p < 0.05) in the percent change of anti-FXa activity normalized to pre-bolus between ANDEXXA and placebo until two hours after administration of infusion.A. Apixaban – with ANDEXXA 400 mg IV bolus plus 4 mg/min infusion for 120 minutes.B. Rivaroxaban – with ANDEXXA 800 mg IV bolus plus 8 mg/min infusion for 120 minutes.

Study 3 ANNEXA-4 (NCT02329327)

In a multinational, prospective, single-arm, open-label study, ANDEXXA was administered to 477

patients taking FXa inhibitors who presented with acute major bleeding.

The co-primary endpoints are: (a) percent change in anti-FXa activity from baseline to the nadir

between five minutes after the end of the bolus up until the end of the infusion; and (b) rate of

effective hemostasis within 12 hours after infusion, as rated by an independent endpoint

adjudication committee.

For the 477 patients dosed with ANDEXXA, 302 were efficacy-evaluable defined as patients (1)

on treatment with apixaban or rivaroxaban; (2) who had a baseline anti-FXa activity above 75

ng/mL; and (3) were adjudicated as meeting eligibility criteria for acute major bleeding [see

Adverse Reactions (6)].

For anti-FXa activity, the median (95% CI) decrease from baseline to nadir in anti-FXa activity for

apixaban was -93% (-94%; -92%) and for rivaroxaban was -94% (-95%; -93%).

An improvement in hemostasis has not been established. ANDEXXA has not been shown to be

effective for bleeding related to any FXa inhibitors other than apixaban or rivaroxaban.

How Supplied

ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) is a white to off-white lyophilized cake or powder supplied as single-dose vials in a carton. ANDEXXA is not made with natural rubber latex.

ANDEXXA vials are provided as follows (see Table 5):

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 5: Presentation of ANDEXXA</span> </caption> <col width="24%"/> <col width="22%"/> <col width="22%"/> <col width="32%"/> <thead> <tr class="First Last"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">NDC</span></th><th align="center" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">Carton Configuration</span></th><th align="center" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">Vial Cap Color</span></th><th align="center" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">Packaging Color</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 0310-3200-04</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">4 single use vials in a carton, each vial containing 200 mg of ANDEXXA</p> </td><td class="Botrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">Vials have a red flip-off cap.</p> </td><td class="Botrule Rrule Toprule" rowspan="2" valign="top"> <dl> <dt>1.</dt> <dd>Carton and vial label have a red to blue transition colored stripe across the front.</dd> <dt>2.</dt> <dd>Carton and label have "200 mg/vial" in a blue graphic on the front panel.</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 0310-3200-05</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">5 single use vials in a carton, each vial containing 200 mg of ANDEXXA</p> </td> </tr> </tbody> </table></div>

Storage and Handling

Prior to reconstitution

Unopened vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F) until the expiration date indicated on the label. DO NOT FREEZE. Do not use ANDEXXA after the expiration date.

After reconstitution

Discuss following with the patient and /or caregivers:

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Manufactured by:

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AstraZeneca AB

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Södertälje, Sweden SE-15185

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Distributed by:

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AstraZeneca Pharmaceuticals LP

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Wilmington, DE 19850

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U.S. License No. 2059

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Product of Spain

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ANDEXXA is a registered trademark of the AstraZeneca group of companies.

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©AstraZeneca 2024

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NDC 0310-3200-04 Rx Only

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ANDEXXA® 200mg/vialcoagulation factor Xa (recombinant), inactivated-zhzo

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Lyophilized powder for solution. For intravenous use only.

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Four 200 mg single-dose vials. Contains no preservative. AstraZeneca

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